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MiR-222 modulates multidrug resistance in human colorectal carcinoma by down-regulating ADAM-17
1State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of pharmacy, East China University of Science and Technology, Shanghai, PR China.
Abstract:
Colorectal carcinoma is a frequent cause of cancer-related death in men and women throughout the world. MicroRNAs are endogenous small noncoding RNAs that negatively regulate gene expression at the posttranscriptional level. We investigated the role of ADAM-17 (a desintegrin and metalloproteases 17) as a novel multidrug resistance (MDR) mechanism in multidrug-resistant colorectal carcinoma (CRC) and the role of miR-222 in the development of MDR in CRC cells. We found that the high expression of ADAM-17, which results in growth factor shedding and growth factor receptor activation could induce drug resistance in CRC. Pharmacological inhibition of ADAM-17, in conjunction with chemotherapy, may have therapeutic potential for the treatment of CRC. ADAM-17 is a predicted target of miR-222, which was downregulated in multidrug-resistant CRC cells. The presence of miR-222 was consistently inversely proportionate to the expression levels of ADAM-17. We found that elevated levels of miR-222 in the mimics-transfected HCT116/L-OHP and HCT-8/VCR cells reduced the ADAM-17 protein level and the luciferase activity of an ADAM-17 3' untranslated region-based reporter and sensitized these cells' apoptosis to some anticancer drugs. Our findings suggest that miR-222 could play a role in the development of MDR by modulation of ADAM-17, the new MDR treatment target in colorectal carcinoma cells.
Insights
MicroRNAs, specifically miR-222, can overcome multidrug resistance (MDR) in colorectal cancer (CRC) by downregulating ADAM-17. This finding offers a new therapeutic target for improving CRC treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Colorectal carcinoma (CRC) is a leading cause of cancer mortality worldwide.
- MicroRNAs regulate gene expression posttranscriptionally.
- Multidrug resistance (MDR) is a significant challenge in CRC treatment.
Purpose of the Study:
- To investigate the role of ADAM-17 as a multidrug resistance mechanism in CRC.
- To explore the function of miR-222 in the development of MDR in CRC cells.
- To assess the therapeutic potential of targeting ADAM-17 and miR-222 in CRC.
Main Methods:
- Investigated ADAM-17 expression in multidrug-resistant CRC cells.
- Analyzed the correlation between miR-222 expression and ADAM-17 levels.
- Utilized miR-222 mimics to transfect CRC cells (HCT116/L-OHP, HCT-8/VCR).
- Assessed ADAM-17 protein levels and luciferase activity of an ADAM-17 3' UTR reporter.
- Evaluated drug sensitivity and apoptosis induction in transfected cells.
Main Results:
- High ADAM-17 expression was found to induce drug resistance in CRC.
- miR-222 was downregulated in multidrug-resistant CRC cells, inversely correlating with ADAM-17 levels.
- Overexpression of miR-222 reduced ADAM-17 protein levels and activity.
- miR-222 mimics sensitized CRC cells to anticancer drugs, promoting apoptosis.
Conclusions:
- miR-222 plays a role in overcoming MDR in colorectal carcinoma by modulating ADAM-17.
- ADAM-17 represents a novel therapeutic target for reversing MDR in CRC.
- Targeting the miR-222/ADAM-17 axis holds therapeutic promise for CRC treatment.
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